Insulin is secreted from β cells of the pancreatic islets of Langerhans and reduces blood sugar level by mainly acting upon muscle, the liver and adipose and thereby incorporating blood sugar into cells to effect its storage and consumption. Diabetes mellitus is induced by insufficient action of this insulin, and two types are present in its patients, namely type 1 having a disorder of the production or secretion of insulin and type 2 having a difficulty in accelerating carbohydrate metabolism by insulin. The blood sugar level in both of these patients becomes higher than that in healthy person, but while insulin in blood is absolutely insufficient in type 1, insulin resistance occurs in type 2 in which incorporation or consumption of blood sugar by cells is not accelerated in spite of the presence of insulin. The type 2 diabetes mellitus is a so-called lifestyle-related disease which is generated due to overeating, lack of exercise, stress and the like causes in addition to the hereditary predisposition. Nowadays, patients of this type 2 diabetes mellitus are rapidly increasing in advanced nations accompanied by the increase of ingestion calories, and this type occupies 95% of diabetes mellitus patients in Japan. Accordingly, necessity is increasing not only for a simple hypoglycemic drug as a therapeutic agent for diabetes mellitus but also on a study which aims at treating type 2 diabetes mellitus for the purpose of accelerating carbohydrate metabolism through the improvement of insulin resistance.
At present, insulin injections are prescribed for the treatment of type 1 diabetes mellitus patients. On the other hand, in addition to the insulin injections, sulfonylurea hypoglycemic agents (SU preparations) which prompts secretion of insulin by acting upon β cells of the pancreas and biguanide hypoglycemic agents which have actions to increase sugar usage and inhibit gluconeogenesis by anaerobic glycolysis action and to inhibit intestinal absorption of sugar, as well as α-glucosidase inhibitors which delay digestion and absorption of saccharides, are known as the hypoglycemic agents prescribed for type 2 patients. Though these indirectly improve insulin resistance, thiazolidine derivatives have been used in recent years as agents which directly improve insulin resistance. Its action is to accelerate incorporation of glucose into cells and use of glucose in cells. It is shown that the thiazolidine derivatives act as an agonist of peroxisome proliferator responding activated receptor gamma (PPARγ) (cf. Non-patent reference 1). However, it is known that the thiazolidinediones not only improve insulin resistance but also have a side effect to induce edema (cf. Non-patent reference 2, Non-patent reference 3). Since this induction of edema is a serious side effect which results in cardiac hypertrophy, more useful target molecule for drug development than the PPARγ is in demand for the improvement of insulin resistance.
The signal of insulin action is transferred into cells via an insulin receptor on the cell membrane. Two pathways of the first and second are present in this insulin action pathway (cf. Non-patent reference 4). In the first pathway, the signal is transferred in order from the activated insulin receptor to Akt1 (PKBα) or Akt2 (PKBβ), or PKCγ or PKCζ, via IRS-1, IRS-2, PI 3 kinase and PDK 1, and incorporation of sugar from the extracellular moiety is accelerated as the result by translocating a glucose transporter GLUT 4 existing inside the cell onto the cell membrane (cf. Non-patent reference 5). On the other hand, in the second pathway, the signal is transferred from the insulin receptor to CrK II, C3G and TC 10 in that order via c-Cbl and CAP, and incorporation of sugar by GLUT 4 is accelerated as the result (cf. Non-patent reference 6). However, there are portions still unclear regarding details of these insulin signal transduction pathways, and it is not clear particularly about the mechanism which finally mediates acceleration of sugar incorporation of cells by these signals via the glucose transporter.
Akt2 is present in the aforementioned insulin signal first pathway and activated by undergoing phosphorylation by insulin stimulation via PDK 1. The activated Akt2 transfers the signal as a kinase by phosphorylating a protein as its substrate. It has been reported that a homo-knockout mouse in which a gene coding for the Akt2 protein was artificially deleted shows a type 2 diabetes-like phenotype due to reduced insulin sensitivity mainly in muscle and the liver. Based on these facts, it has been considered that Akt2 is a signal mediating factor which functions in incorporating sugar into cells in response to the insulin signal, and its functional inhibition induces insulin resistance by partial interception of the insulin signal transduction (cf. Non-patent reference 7).
(Non-patent Reference 1)
“The Journal of Biological Chemistry”, (USA), 1995, vol. 270, pp. 12953-12956
(Non-patent Reference 2)
“Diabetes Frontier”, (USA), 1999, vol. 10, pp. 811-818
(Non-patent Reference 3)
“Diabetes Frontier”, (USA), 1999, vol. 10, pp. 819-824
(Non-patent Reference 4)
“The Journal of Clinical Investigation”, (USA), 2000, vol. 106, no. 2, pp. 165-169
(Non-patent Reference 5)
“The Journal of Biological Chemistry”, (USA), 1999, vol. 274, no. 4, pp. 1865-1868
(Non-patent Reference 6)
“Nature”, (England), 2001, vol. 410, no. 6831, pp. 944-948
(Non-patent Reference 7)
“Science”, (USA), 2002, vol. 292, no. 2, pp. 1728-1731